Mast cell involvement in most allergic events typically occurs due to IgE-mediated activation of such cells. However, recent progress reveals that mast cells play important roles in innate as well as acquired immunity. Complement activation also occurs during both innate and acquired immunity. In the murine system, C3 and C5 deficiencies affect mast cells in various ways, such as reducing cytokine release and the efficiency with which they kill bacteria. Our preliminary data show that human mast cells synthesize complement C3, C4 and C5, and express complement regulatory proteins, CD46, CD55, CD59 and CR1. Specific Aim 1 will analyze complement synthesis by human mast cells, including the effect(s) of cytokines and other stimulants on complement synthesis by skin MCTC cells and lung MCT cells, how endogenous complement proteins affect mast cell activation with respect to degranulation, cytokine release, chemokine release and production of reactive oxygen species and whether complement regulatory proteins affect mast cell activation. Specific Aim 2 will analyze which matrix metalloproteases activate complement on human mast cells. The interactions between mast cells and the complement system may have important implications for disorders in which both complement and mast cells are activated, such as asthma and chronic autoimmune urticaria. PUBLIC HEALTH RELEVANCE: Asthma is a major problem in the United States and also in the world. Both mast cells and complement are involved in the pathogenesis of asthma. The goal of this proposal is to better understand how the human complement pathway interacts with human mast cells.